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My name is Madison Etheridge, and I am 15 years old. I was born with cerebral palsy. Cerebral palsy is caused by damage to the brain, which usually occurs during [...]

There is a pressing need for ecologically valid versions of traditional neuropsychological tests indexing executive function (EF), such as the Trail-Making Task (TMT), that incorporate movement and bodily awareness in healthy participants with varying abilities. We designed a proprioceptive version of the TMT (pTMT) that involved coordinated gross motor movement and proprioceptive awareness to investigate whether this measure of visual attention, task switching, and working memory positively correlated with a computerized version of the TMT (the dTMT). We aimed to establish the initial validity of our proprioceptive TMT (pTMT) by comparing performances on the dTMT and pTMT among a cohort of 36 healthy participants (18 dancers, 18 non-dancers; Mage = 22, SD= 5.27; 64% female) anticipating that dancers would express higher intrinsic bodily awareness than non-dancers. Results revealed a mild to moderate but statistically significant positive correlation between dTMT and pTMT completion times [part A: r (36) = .33, p= .04; part B: r (36) = .37, p= .03] and numbers of errors [part B: r (36) = .41, p= .01] across both participant groups. These data suggest partial measurement convergence between these two TMT versions. Relative to non-dancers, dancers exhibited a higher level of performance (likely due to their better proprioceptive ability) through their faster completion times on dTMT-B [t (34) = 3.81, p= .006, d= 1.27] and pTMT-B [t(34) = 2.97, p= .005, d= .99], and their fewer errors on dTMT-B [t(34) = 2.93, p= .006, d= 1.0]. By identifying cognitive differences between these different groups of healthy individuals, our data contribute to both a theoretical understanding and the initial development of gross motor movement-based cognitive assessments, providing a path toward the further refinement of an ecologically valid full-body TMT.

The Sandusky River, Ohio, is one of the major Lake Erie tributaries that supports migratory Walleye Sander vitreusreproduction. Following the construction of the Ballville Dam in 1913, Walleye spawning was limited to an area downstream near Fremont, Ohio. After the removal of the dam in 2018, several natural and human‐made features were identified that may impede Walleye passage by collecting woody debris and altering flow conditions. In this study, we use hydrologic modeling and migratory sampling to understand the spatial and temporal dynamic nature of the blockages caused by the remaining anthropogenic and natural barriers. We created a fine‐scale Hydrologic Engineering Center's River Analysis System (HEC‐RAS) model to examine these potential natural and human‐made barriers to Walleye passage during spawning. Using our model, we compared swim speeds (10 min maintained and burst) of small, medium, and large Walleye under three flow scenarios with five levels of blockage to assess whether the area was passable. Further, we conducted electrofishing surveys during annual spawning runs from 2020 to 2021 to assess Walleye presence upstream and downstream after dam removal. Our model predicted that Walleye were able to pass the barriers under most of the scenarios by maintaining burst swim speed. Additionally, we captured Walleye above the former dam site in 2021, suggesting that Walleye can access newly available spawning habitat during certain river conditions. Removing the Ballville Dam restored fish passage, increased access to spawning habitat, and could improve Walleye production in the Sandusky River. Impact statementFollowing the removal of a long‐standing dam, installation of ice control structures and presence of natural barriers on the Sandusky River has changed flow and created selective barriers to migratory Walleye. Our study uses velocity models and presence of Walleye to further understand the nature of these dynamic barriers. Following the removal of a long‐standing dam, installation of ice control structures and presence of natural barriers on the Sandusky River has changed flow and created selective barriers to migratory Walleye. Our study uses velocity models and presence of Walleye to further understand the nature of these dynamic barriers.

Background: Virtual reality (VR) has been explored to improve baseline and postinjury assessments in sport-related concussion (SRC). Some experience symptoms related to VR, unrelated to concussion. This may deter use of vestibular/ocular motor screening (VOMS) using VR. Baseline VR VOMS symptomatology differentiates baseline from overall symptomatology.Hypothesis: There will be no difference between current clinical manual VOMS (MAN), a clinical prototype (PRO), and VR for symptom provocation change score (SPCS) and near point of convergence (NPC) average score in a healthy population and sex differences among the 3 modes of administration.Study Design: Cohort study.Level of Evidence: Level 3.Methods: A total of 688 National Collegiate Athletic Association Division I student-athletes completed VOMS using 3 methods (MAN, N = 111; female athletes, N = 47; male athletes, N = 64; average age, 21 years; PRO, N = 365; female athletes, N = 154; male athletes, N = 211; average age, 21 years; VR, N = 212; female athletes, N = 78; male athletes, N = 134; average age = 20 years) over a 3-year period (2019-2021) during annual baseline testing. Exclusion criteria were as follows: self-reported motion sickness in the past 6 months, existing or previous neurological insult, attention deficit hyperactivity disorder, learning disabilities, or noncorrected vision impairment. Administration of MAN followed the current clinical protocols, PRO used a novel prototype, and VR used an HTC Vive Pro Eye head mounted display. Symptom provocation was compared using Mann-Whitney Utests across each VOMS subtest with total SPCS and NPC average by each method.Results: MAN had significantly (P< 0.01) more baseline SPCS (MAN = 0.466 ± 1.165, PRO = 0.163 ± 0.644, VR = 0.161 ± 0.933) and significantly (P< 0.01) and more SPCS (MAN = 0.396 ± 1.081, PRO = 0.128 ± 0.427, VR = 0.48 ± 0.845) when compared with PRO and VR. NPC average measurements for VR (average, 2.99 ± 0.684 cm) were significantly greater than MAN (average, 2.91 ± 3.35 cm; P< 0.01; Cohen’s d = 0.03) and PRO (average, 2.21 ± 1.81 cm; P< 0.01; Cohen’s d = 0.57). For sex differences, female athletes reported greater SPCS with PRO (female athletes, 0.29 ± 0.87; male athletes, 0.06 ± 0.29; P< 0.01) but not in VR or MAN.Conclusion: Using a VR system to administer the VOMS may not elicit additional symptoms, resulting in fewer false positives and is somewhat stable between sexes.Clinical Relevance: VOMS may allow for standardization among administrators and reduce possible false positives.

IMPORTANCE: Firearm violence is increasingly recognized as a public health issue, but whether physicians should intervene remains politically contested. OBJECTIVE: To explore self-described patient perspectives about the appropriateness and acceptability of health care screening for firearms. DESIGN, SETTING, AND PARTICIPANTS: This qualitative study recruited 50 adult patients from a primary care clinic in Chicago, Illinois, from June 7, 2019, to January 11, 2021, to participate in 1 of 12 one-time qualitative focus groups. Focus group discussions were facilitated using an in-depth, semistructured guide, transcribed verbatim from audio recordings, and analyzed for major themes using a pragmatic approach to basic thematic analysis, which is commonly used in implementation science, between December 12, 2019, and November 29, 2022. MAIN OUTCOMES AND MEASURES: Patient perspectives of health care screening for firearms were evaluated to examine complexities of a practice change goal. RESULTS: Participants were a median age of 60.0 (IQR, 50.5-66.5) years and predominantly female (37 [74%]; male, 11 [22%]; nonbinary, 1 [2%]; transgender, 1 [2%]) and non-Hispanic Black (42 [84%]; non-Hispanic Asian or Pacific Islander, 2 [4%]; non-Hispanic White, 5 [10%]). Two-thirds (32 [64%]) of participants thought that health care screening for firearms was at least sometimes appropriate, recognizing clear benefits, for instance, among patients at risk for suicide. However, few (2 [4%]) had ever discussed firearms with a physician or other health care professional. Even among those who recognized benefits, several barriers to acceptability were described, especially related to bias, stigma, and increased risk for criminal legal involvement. Other major themes included insufficient time to address firearms during health care visits and doubts about a clinician’s ability to intervene. Facilitators to acceptability included screening strategies that were patient centered, sensitive to racial bias, clinically efficient, and accompanied by tangible resources. CONCLUSIONS AND RELEVANCE: Incorporating these findings and emergent themes into clinical practice may guide efforts to make firearm screening more acceptable for patients from historically marginalized communities.

CYP2C19genotyping to guide antiplatelet therapy after patients develop acute coronary syndromes (ACS) or require percutaneous coronary interventions (PCIs) reduces the likelihood of major adverse cardiovascular events (MACE). Evidence about the impact of preemptive testing, where genotyping occurs while patients are healthy, is lacking. In patients initiating antiplatelet therapy for ACS or PCI, we compared medical records data from 67 patients who received CYP2C19genotyping preemptively (results >7 days before need), against medical records data from 67 propensity score-matched patients who received early genotyping (results within 7 days of need). We also examined data from 140 patients who received late genotyping (results >7 days after need). We compared the impact of genotyping approaches on medication selections, specialty visits, MACE and bleeding events over 1 year. Patients with CYP2C19loss-of-function alleles were less likely to be initiated on clopidogrel if they received preemptive rather than early or late genotyping (18.2%, 66.7%, and 73.2% respectively, p= 0.001). No differences were observed by genotyping approach in the number of specialty visits or likelihood of MACE or bleeding events (all p> 0.21). Preemptive genotyping had a strong impact on initial antiplatelet selection and a comparable impact on patient outcomes and healthcare utilization, compared to genotyping ordered after a need for antiplatelet therapy had been identified.

Lung cancer represents a large burden on society with a staggering incidence and mortality rate that has steadily increased until recently. The impetus to design an effective screening program for the deadliest cancer in the United States and worldwide began in 1950. It has taken more than 50 years of numerous clinical trials and continued persistence to arrive at the development of modern-day screening program. As the program continues to grow, it is important for clinicians to understand its evolution, track outcomes, and continually assess the impact and bias of screening on the medical, social, and economic systems.

Purpose: This investigation sought to compare admissions, length of stay, and mortality among medical intensive care unit (MICU) patients without coronavirus disease 2019 (COVID-19) infection admitted to an urban safety-net hospital during the pandemic by patients’ self-identified race and ethnicity. Materials and Methods: We conducted a retrospective observational study comparing MICU admissions before and during the first surge of COVID-19 illness at an urban, safety-net hospital in Minneapolis, Minnesota. Results: MICU admissions declined from a pre-pandemic average of 968 to 761 during the first COVID surge, including 627 patients (82%) without COVID-19 infection. MICU mortality among patients without COVID-19 infection during the pandemic was 12.8% compared to 9.6% in the pre-pandemic period (p= 0.045). However, rates of non-COVID-19 MICU admissions, mortality, volume, and length of stay did not differ by race and ethnicity between time periods. Of the 131 MICU admissions with COVID-19 infection, patients were more frequently Hispanic ethnicity (24%) or Black (40%), and less frequently White (22%) compared to the pre-pandemic cohort (7%, 30%, and 48%, respectively [p&lt; 0.001]). Conclusions: During the first COVID-19 surge, MICU admissions for non-COVID-19 disease decreased from pre-pandemic levels, but these patients experienced greater mortality. Unlike critically ill patients admitted with COVID-19 infection, admissions and hospital mortality did not differ by race and ethnicity compared to the pre-pandemic period.

Aim:To understand how attitudes toward pharmacogenomic (PGx) testing among healthcare providers varies by specialty. Methods:Providers reported comfort ordering PGx testing and its perceived utility on web-based surveys before and after genetics education. Primary quantitative analyses compared primary care providers (PCPs) to specialty providers at both timepoints. Results:PCPs were more likely than specialty care providers to rate PGx testing as useful at both timepoints. Education increased comfort ordering PGx tests, with larger improvements among PCPs than specialty providers. Over 90% of cardiology and internal medicine providers rated PGx testing as useful at pre- and post-education. Conclusion:PCPs overwhelmingly perceive PGx to be useful, and provider education is particularly effective for improving PCPs' confidence. Education for all specialties will be essential to ensure appropriate integration into routine practice.

Background:SLCO1B1variants are known to be a strong predictor of statin-associated muscle symptoms (SAMS) risk with simvastatin. Methods:The authors conducted a retrospective chart review on 20,341 patients who had SLCO1B1genotyping to quantify the uptake of clinical decision support (CDS) for genetic variants known to impact SAMS risk. Results:A total of 182 patients had 417 CDS alerts generated, and 150 of these patients (82.4%) received pharmacotherapy that did not increase risks for SAMS. Providers were more likely to cancel simvastatin orders in response to CDS alerts if genotyping had been done prior to the first simvastatin prescription than after (94.1% vs 28.5%, respectively; p < 0.001). Conclusion:CDS significantly reduces simvastatin prescribing at doses associated with SAMS.

Many RNA delivery strategies require efficient endosomal uptake and release. To monitor this process, we developed a 2′-OMe RNA-based ratiometric pH probe with a pH-invariant 3′-Cy5 and 5′-FAM whose pH sensitivity is enhanced by proximal guanines. The probe, in duplex with a DNA complement, exhibits a 48.9-fold FAM fluorescence enhancement going from pH 4.5 to pH 8.0 and reports on both endosomal entrapment and release when delivered to HeLa cells. In complex with an antisense RNA complement, the probe constitutes an siRNA mimic capable of protein knockdown in HEK293T cells. This illustrates a general approach for measuring the localization and pH microenvironment of any oligonucleotide.

Elective genomic testing (EGT) is increasingly available clinically. Limited real-world evidence exists about attitudes and knowledge of EGT recipients.

Background:The purpose of this study was to develop and validate reliable computed tomography (CT) imaging criteria for the diagnosis of gastric band slippage. Material and Methods:We retrospectively evaluated 67 patients for gastric band slippage using CT. Of these, 14 had surgically proven gastric band slippage (study group), 22 had their gastric bands removed for reasons other than slippage (control group 1), and 31 did not require removal (control group 2). All of the studies were read independently by two radiologists in a blinded fashion. The “O” sign, phi angle, amount of inferior displacement from the esophageal hiatus, and gastric pouch size were used to create CT diagnostic criteria. Standard statistical methods were used. Results:There was good overall interobserver agreement for diagnosis of gastric band slippage using CT diagnostic criteria (kappa = 0.83). Agreement was excellent for the “O” sign (kappa = 0.93) and phi angle (intraclass correlation coefficient = 0.976). The “O” sign, inferior displacement from the hiatus >3.5 cm, and gastric pouch volume >55 cm3 each had 100% positive predictive value. A phi angle <20° or >60° had the highest negative predictive value (NPV) (98%). Of all CT diagnostic criteria, enlarged gastric pouch size was most correlated with band slippage with an AUC of 0.991. Conclusion:All four imaging parameters were useful in evaluating for gastric band slippage on CT, with good interobserver agreement. Of these parameters, enlarged gastric pouch size was most correlated with slippage and abnormal phi angle had the highest NPV.

We present DEIMoS: Data Extraction for Integrated Multidimensional Spectrometry, a Python application programming interface (API) and command-line tool for high-dimensional mass spectrometry data analysis workflows that offers ease of development and access to efficient algorithmic implementations. Functionality includes feature detection, feature alignment, collision cross section (CCS) calibration, isotope detection, and MS/MS spectral deconvolution, with the output comprising detected features aligned across study samples and characterized by mass, CCS, tandem mass spectra, and isotopic signature. Notably, DEIMoS operates on N-dimensional data, largely agnostic to acquisition instrumentation; algorithm implementations simultaneously utilize all dimensions to (i) offer greater separation between features, thus improving detection sensitivity, (ii) increase alignment/feature matching confidence among data sets, and (iii) mitigate convolution artifacts in tandem mass spectra. We demonstrate DEIMoS with LC-IMS-MS/MS metabolomics data to illustrate the advantages of a multidimensional approach in each data processing step.

Over a century of metals pollution and channel disturbance associated with historical mining, land use, and water development contributed to degradation of aquatic and riparian habitat within the upper Arkansas River watershed near Leadville, Colorado. Following water quality remediation, habitat restoration was conducted for a 17.7‐km reach characterized as an overwide channel that lacked velocity refuge and overwinter habitat for salmonids. The primary goals of restoration were to improve populations of Brown Trout Salmo truttaand individual fish health, with a target to increase fish metrics by 10% within 5 years after restoration. Fish metrics included Brown Trout density, biomass, quality, and relative weight, where quality was defined as the density of Brown Trout over 356 mm in length. Changes in all fish metrics were evaluated with a before‐after–control‐impact study design that utilized five control sites and five impact sites. Biomass was the only metric that exhibited a significant interaction between site type and period (before and after), with increases of 12% and 21% at control and impact sites, respectively. Increased density (10%) and relative weight (2.4%) were observed across all sites regardless of type. Changes at individual sites were less evident, with only one impact site showing significant increases in biomass (99%) and quality Brown Trout (306%). These results suggest that Brown Trout populations within the upper Arkansas River have continued to improve following large‐scale water quality remediation and stream restoration efforts. Additional monitoring is recommended to evaluate long‐term trends and inform adaptive management.

Children and adolescents with heterogeneous psychiatric disorders, of whom over 50% have a second psychiatric comorbidity, have low rates of physical activity and experience unique challenges to engaging in community-based exercise programming, school-based physical education programming, and targeted physical activity interventions. This contributes to elevated rates of gross and fine motor delays, lower mood and self-regulation, and increased risk of chronic diseases such as obesity and type 2 diabetes. Perform a systematic scoping review of the literature to assess known barriers to and facilitators of engaging in physical activity programming among children and adolescents with heterogeneous and/or comorbid psychiatric disorders, in order to improve engagement among this population in real world intervention settings. Systematic Boolean diagnostic and physical activity search terms were entered into PubMed, MEDLINE, PsycINFO and Web of Science for English-language studies published between 2005 and 2020, examining barriers and facilitators for common psychiatric diagnoses and general psychiatric population’s engagement in physical activity, physical education, sports, or exercise interventions. Two reviewers independently reviewed titles, abstracts and full articles to determine inclusion. A total of 5,198 articles were returned; 39 relating to children and adolescents were qualified for full-text review. After review, 24 studies were included addressing barriers and facilitators across multiple diagnoses; 7 studies were quantitative, 10 were qualitative, and 7 were mixed methods. Major barriers included low motivation, low self-efficacy, depleted parental reserve capacity, social isolation, lack of staff training, and safety concerns. Major facilitators included peer support/engagement, exergames, supportive parental behaviors, and inclusive/adaptive programming. Numerous barriers and facilitators to physical activity have been identified which should inform community, school, clinical, and research intervention program design. Further research is needed to develop effective strategies that address the challenges to inclusion that children and adolescents with heterogeneous and/or comorbid psychiatric disorders face.

This study examined the developmental pathways from fathers’ psychopathology in early childhood to child peer victimization (bullying and cyber victimization) in late adolescence via family relationships and early adolescent psychosocial functioning (anxiety, emotion regulation, social problems). A conceptual model with pathways through inter-parental aggression and fathers’ parenting (harshness and sensitivity) was tested. Participants were 227 families (51% female children recruited as infants) who participated in a longitudinal study examining the role of parental alcohol problems and associated risks on developmental and family processes from infancy to late adolescence. Multi-method (observational, parent report, adolescent report) assessments of family processes and child outcomes were conducted across all time points. Fathers’ alcohol problems and depressive symptoms in early childhood was prospectively associated with inter-parental aggression in middle childhood and social problems in early adolescence. For boys only, early adolescent social problems were predictive of bullying victimization. Fathers’ antisocial behavior in early childhood was associated with less sensitive parenting in middle childhood. Fathers’ sensitivity in middle childhood was protective, being associated with lower cyber victimization in late adolescence. Fathers’ sensitivity was also associated with higher emotion regulation in early adolescence; however, counter to expectations, higher emotion regulation was associated with more bullying and cyber victimization. Findings shed light on differences in the etiological pathways to bullying and cyber victimization, as well as how distinct forms of paternal psychopathology in early childhood associate with family relationships, child adjustment, and vulnerability to peer victimization in late adolescence.

Radiation exposure occurs during medical procedures, nuclear accidents, or spaceflight, making effective medical countermeasures a public health priority. Naïve T cells are highly sensitive to radiation-induced depletion, although their numbers recover with time. Circulating memory CD8+ T cells are also depleted by radiation; however, their numbers do not recover. Critically, the impact of radiation exposure on tissue-resident memory T cells (TRM) remains unknown. Here, we found that sublethal thorax-targeted radiation resulted in the rapid and prolonged numerical decline of influenza A virus (IAV)–specific lung TRM in mice, but no decline in antigen-matched circulating memory T cells. Prolonged loss of lung TRM was associated with decreased heterosubtypic immunity. Importantly, boosting with IAV-epitope expressing pathogens that replicate in the lungs or peripheral tissues or with a peripherally administered mRNA vaccine regenerated lung TRM that was derived largely from circulating memory CD8+ T cells. Designing effective vaccination strategies to regenerate TRM will be important in combating the immunological effects of radiation exposure.

Background: There are approximately 2.1 million recreational surfers in the United States. However, little has been reported on surfing-related injuries and, to date, no study has utilized magnetic resonance imaging (MRI) to characterize injury patterns.Objective: To use MRI to perform a descriptive analysis of surfing injuries in patients who presented to an urban tertiary care musculoskeletal hospital. This was not a hypothesis-driven study.Study Design: Case series.Level of Evidence: Level 4.Methods: A retrospective review of the picture archiving and communication system as well as the electronic medical record was performed to identify patients with surfing-related injuries who presented to a tertiary care musculoskeletal hospital for treatment. The search included participants over a 10-year period who presented between January 1, 2009, and August 1, 2018. Descriptive data analyses were performed to determine frequency of body part injured, diagnosis, and operative versus nonoperative treatment.Results: The search yielded 109 patients with surfing-related injuries and MRIs. A total of 90 patients presented within 6 months of their surfing injury and were included in the final analysis. The median age was 36 years (range, 12-66 years). A majority of the patients included were male (74%; n = 67). Acute surfing injuries were diagnosed via imaging in 72% (n = 65) of patients. The joints injured most commonly were the shoulder (46%; n = 30) and the knee (28%; n = 18). Only 17% (n = 11) of acute surfing injuries required surgery, while 83% (n = 54) were treated nonoperatively.Conclusion: The most common surfing-related injuries occurred in the shoulder and knee.Clinical Relevance: This study helps characterize the risk of injury for surfers and informs healthcare providers on common surfing injuries.

Organic electrode materials have emerged as attractive alternatives to electrodes in lithium-ion batteries produced from toxic and unsustainably sourced transition metals. However, low-molecular-weight organic compounds still lack the cycling stability and high-rate capability found in transition-metal electrodes. Herein, we report S-rich thiazyl moieties as a new design feature for small-molecule organic electrode materials. Our findings suggest that S-rich thiazyl moieties engender strong intermolecular interactions that contribute to the insolubility and fast charging of low-molecular-weight quinones. This is demonstrated by the contrasting performance of three isomorphic bisthiazolyl quinones in the solid state: the quinone with the strongest intermolecular interactions can be cycled at a high rate of 10 C for 400 cycles with a 94% capacity retention, while those with weak intermolecular interactions suffer from dissolution and low cycling stabilities (<20 cycles). Our study reveals that S-rich thiazyl moieties may be used to design low-molecular-weight organic electrode materials to achieve long cycle life and fast electrode kinetics.

The amyloid-β (Aβ) peptide is a cleavage product of the amyloid precursor protein and has been implicated as a central player in Alzheimer’s disease. The N-terminal end of Aβ is variable, and different proportions of these variable-length Aβ peptides are present in healthy individuals and those with the disease. The N-terminally truncated form of Aβ starting at position 4 (Aβ4–x) has a His residue as the third amino acid (His6 using the formal Aβ numbering). The N-terminal sequence Xaa-Xaa-His is known as an amino terminal copper and nickel binding motif (ATCUN), which avidly binds Cu(II). This motif is not present in the commonly studied Aβ1–xpeptides. In addition to the ATCUN site, Aβ4–xcontains an additional metal binding site located at the tandem His residues (bis-His at His13 and 14) which is also found in other isoforms of Aβ. Using the ATCUN and bis-His motifs, the Aβ4–xpeptide is capable of binding multiple metal ions simultaneously. We confirm that Cu(II) bound to this particular ATCUN site is redox silent, but the second Cu(II) site is redox active and can be readily reduced with ascorbate. We have employed surrogate metal ions to block copper coordination at the ATCUN or the tandem His site in order to isolate spectral features of the copper coordination environment for structural characterization using extended X-ray absorption fine structure (EXAFS) spectroscopy. This approach reveals that each copper coordination environment is independent in the Cu2Aβ4–xstate. The identification of two functionally different copper binding environments within the Aβ4–xsequence may have important implications for this peptide in vivo.

The role of medial prefrontal cortex (mPFC) in regulating nicotine taking and seeking remains largely unexplored. In this study we took advantage of the high time-resolution of optogenetic intervention by decreasing (Arch3.0) or increasing (ChR2) the activity of neurons in the dorsal and ventral mPFC during 5-s nicotine cue presentations in order to evaluate their contribution to cued nicotine seeking and taking. Wistar rats were trained to self-administer intravenous nicotine in 1?h self-administration sessions twice a day for a minimum of 10 days. Subsequently, dmPFC or vmPFC neuronal activity was modulated during or following presentation of the 5-s nicotine cue, both under extinction and self-administration conditions. We also used in vivo electrophysiology to record the activity of dmPFC neurons during nicotine self-administration and extinction tests. We show that optogenetic inhibition of dmPFC neurons during, but not following, response-contingent presentations of the nicotine cue increased nicotine seeking. We found no effect on nicotine self-administration or on food seeking in an extinction test. We also show that this effect is specific to dmPFC, because optogenetic inhibition of vmPFC had no effect on nicotine seeking and taking. In vivo recordings revealed that dmPFC network neuronal activity was modulated more strongly following nicotine cue presentation in extinction, compared to following nicotine self-administration. Our results strongly suggest that a population of neurons within the dmPFC is involved in encoding the incentive value of nicotine-associated cues.

Inflammatory bowel disease (IBD) can present as either Crohn’s disease or ulcerative colitis. Both phenotypes are inflammatory conditions of the gastrointestinal tract that can result in symptoms including abdominal pain, diarrhea, rectal bleeding and fatigue. Despite scientific advances, the overall incidence and morbidity of IBD continues to increase worldwide. And, despite the similarly ever-growing number of approved biologic therapies, we have yet to make significant strides in efficacy as seen by a steady state of corticosteroid use, hospitalizations, and need for surgical intervention. Fortunately, we continue to develop novel therapies, in hopes of providing safer, more effective, treatment options. Such therapies include cell therapy, exosome therapy, hyperbaric oxygen therapy and central nerve stimulation. The aim of this review is to briefly highlight each of these novel therapeutic interventions as they relate to the treatment of IBD.

Background: This study evaluated 2 different dual-task (DT) conditions during tandem gait (TG) to predict sport-related concussion (SRC) diagnosis.Hypothesis: The best (fastest) single-task (ST) gait will differ between groups (controls vs SRC; baseline vs SRC), with auditory pure switching task (APST) response rate being the most important behavioral variable to aid prediction of SRC.Study Design: Cohort design.Level of Evidence: Level 3.Methods: A total of 409 National Collegiate Athletic Association Division I student-athlete controls and 21 team-physician-diagnosed SRC participated. All data were collected at preseason physicals (baseline) and within 7 days of injury for SRC. Each participant completed 3 conditions of TG in a pseudorandomized order: (1) ST, (2) DT with serial-7s (SS) subtractions, and (3) DT with APST. Outcomes of time-to-complete for TG and behavioral (eg, responses per second) for SS and APST were recorded for each trial.Results: ST Trials 2 (P= 0.03) and 3 (P= 0.01) were significantly different between controls and SRC. ST Trial 3 (P= 0.04) was significantly different between baseline and SRC. Average responses per second for APST were significantly different between- (P< 0.01) and within- (P= 0.01) group.Conclusion: The results suggest that ST is significantly slower after SRC. However, DT (both SS and APST) time-to-complete are also important variables when predicting the SRC diagnosis. It is advised that both ST and DT be administered when making clinical decisions regarding postural instability after SRC.Clinical Relevance: The best ST TG time to complete gait is an important objective marker of concussion while DT paradigms, specifically SS and APST, are highly variable. DT may be more useful for clinical observable signs of SRC. Both SS and APST have unique usefulness, but APST response rate per second can be relied upon numerically for clinical decisions.

We present the investigation of 1,2,4,5-tetrazine derivatives as low-cost and synthetically modular organic electrode materials in rechargeable aqueous Zn-ion batteries (AZIBs). The substituents at the 3,6-positions of tetrazine were found to be critical for cycling stability. While heteroatom substituents (chloro, methoxy, and pyrazole) lead to the rapid decomposition of electrode materials in the electrolyte, the installation of phenyl groups enhances the cycling stability via π–π stacking. Spectroscopic characterization suggests a cooperative Zn2+and H+insertion mechanism. This unique cooperativity of Zn2+and H+leads to a steady discharge plateau in contrast to the undesirable sloping voltage profile typically observed in Zn-organic batteries.

Enantioenriched aldehydes are produced through asymmetric hydroformylation of styrene derivatives using BIBOP-type ligands. The featured example is enantioselective synthesis of 4-methyl-3,4-dihydroisocoumarin, which was prepared in a 95.1:4.9 enantiomeric ratio from asymmetric hydroformylation of ethyl 2-vinylbenzoate followed by in situ lactonization during the reduction process. The conditions are compatible with both electron-rich and electron-poor substituents.

The evolution of a more reactive chiral vanadium catalyst for enantioselective oxidative coupling of phenols is reported, ultimately resulting in a simple monomeric vanadium species combined with a Brønsted or Lewis acid additive. The resultant vanadium complex is found to effect the asymmetric oxidative ortho–orthocoupling of simple phenols and 2-hydroxycarbazoles with good to excellent levels of enantioselectivity. Experimental and quantum mechanical studies of the mechanism indicate that the additives aggregate the vanadium monomers. In addition, a singlet to triplet crossover is implicated prior to carbon–carbon bond formation. The two lowest energy diastereomeric transition states leading to the enantiomeric products differ substantially with the path to the minor enantiomer involving greater torsional strain between the two phenol moieties.

Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls.

Studies manipulating neural activity acutely with optogenetic or chemogenetic intervention in behaving rodents have increased considerably in recent years. More often, these circuit-level neural manipulations are tested within an existing framework of behavioural testing that strives to model complex executive functions or symptomologies relevant to multidimensional psychiatric disorders in humans, such as attentional control deficits, impulsivity or behavioural (in)flexibility. This methods perspective argues in favour of carefully implementing these acute circuit-based approaches to better understand and model cognitive symptomologies or their similar isomorphic animal behaviours, which often arise and persist in overlapping brain circuitries. First, we offer some practical considerations for combining long-term, behavioural paradigms with optogenetic or chemogenetic interventions. Next, we examine how cell-type or projection-specific manipulations to the ascending neuromodulatory systems, local brain region or descending cortical glutamatergic projections influence aspects of cognitive control. For this, we primarily focus on the influence exerted on attentional and motor impulsivity performance in the (3-choice or) 5-choice serial reaction time task, and impulsive, risky or inflexible choice biases during alternative preference, reward discounting or reversal learning tasks.

The average age of onset of multiple sclerosis (MS) is between 20 and 40 years of age. Therefore, most new patients diagnosed with MS within the next 10 to 15 years will be from the millennial generation, representing those born between 1982 and 2000. Certain preferences and trends of this contemporary generation will present new challenges to the MS physician and effective MS care. By first understanding these challenges, relevant and successful solutions can be created to craft a system of care that best benefits the millennial patient with MS.

From the inception of the Constitution, the United States has protected inventions in the form of patent rights. For many years, innovation thrived and protections for patent rights continued to expand. However, beginning in 2012, the Supreme Court decisions of Mayo, Myriad, and Alice created a new barrier for what can be considered patent-eligible subject matter. These decisions completely undermined the patent system and made obtaining a patent an impossibility for several fields of invention. By focusing on one type of technology--natural products--this Note examines the recent subject-matter eligibility decisions from the Supreme Court and the impact they have had on patent eligibility of natural products. This Note also discusses why those decisions were fundamentally made in error and proposes several solutions to the problem. While the problem the Supreme Court created is far more complicated than this Note could hope to address, it is apparent that Congress needs to intervene in order for the United States to remain competitive in the global economy by incentivizing advances in technology. [ABSTRACT FROM AUTHOR]

The cobalt-catalyzed asymmetric hydrogenation of indazole-containing enamides relevant to the synthesis of the calcitonin gene-related peptide (CGRP) receptor antagonist, zavegepant (1), approved for the treatment of migraines, is described. Both neutral bis(phosphine)cobalt(II) and cationic bis(phosphine)cobalt(I) complexes served as efficient precatalysts for the enamide hydrogenation reactions, providing excellent yield and enantioselectivities (up to >99.9%) for a range of related substrates, though key reactivity differences were observed. Hydrogenation of indazole-containing enamide, methyl (Z)-2-acetamido-3-(7-methyl-1H-indazol-5-yl)acrylate, was performed on a 20 g scale.

The polymer-composite binder used in lithium-ion battery electrodes must both hold the electrodes together and augment their electrical conductivity while subjected to mechanical stresses caused by active material volume changes due to lithiation and delithiation. We have discovered that cyclic mechanical stresses cause significant degradation in the binder electrical conductivity. After just 160 mechanical cycles, the conductivity of polyvinylidene fluoride (PVDF):carbon black binder dropped between 45-75%. This degradation in binder conductivity has been shown to be quite general, occurring over a range of carbon black concentrations, with and without absorbed electrolyte solvent and for different polymer manufacturers. Mechanical cycling of lithium cobalt oxide (LiCoO2) cathodes caused a similar degradation, reducing the effective electrical conductivity by 30-40%. Mesoscale simulations on a reconstructed experimental cathode geometry predicted the binder conductivity degradation will have a proportional impact on cathode electrical conductivity, in qualitative agreement with the experimental measurements. Finally, ohmic resistance measurements were made on complete batteries. Direct comparisons between electrochemical cycling and mechanical cycling show consistent trends in the conductivity decline. This evidence supports a new mechanism for performance decline of rechargeable lithium-ion batteries during operation - electrochemically-induced mechanical stresses that degrade binder conductivity, increasing the internal resistance of the battery with cycling.

Objectives of this study were to evaluate birth weight (BW), weaning weight (WW), and average daily weight gain (ADG) of female calves carrying the SLICK1 allele, i.e., the slick gene. Holstein cows in four dairy farms located in central California were inseminated with semen from two heterozygous slick Holstein sires to produce slick and non-slick calves. Calves were born during the cool season (November 2019-March 2020). BW was recorded for 125 calves in four farms within 24 h of birth; WW was recorded for 92 calves in three farms within one week of weaning. Weaning age was recorded at day of weighing. ADG was calculated as the weight difference between birth and weaning divided by days of age at weaning. Only female calves were used in the analysis. Statistical analyses were performed using the GLIMMIX procedure of SAS version 9.4. The model for BW included the effects of genotype, farm, sire, and the interaction between genotype and farm. The model for WW and ADG included the effects of BW, genotype, farm, weaning age, sire, and interaction between genotype and farm. Significant effects were considered as those with P < 0.05. There was no difference in BW or WW between genotypes (BW: slick=40.1 ± 0.7 vs non-slick=39.7 ± 0.6 kg; P = 0.7 and WW: slick=82.5 ± 2.8 vs non-slick=80.9 ± 2.8 kg; P = 0.6). The mean age at weaning was 64.8 ± 0.4 and was similar for both genotype groups (P = 0.8). As a result, ADG was similar between genotypes (P = 0.7). There was a main effect of farm on BW, WW and ADG. Results indicate that slick heifer calves born in the cool season perform similarly to non-slick calves in regards to birth weight, average daily weight gain, and weaning weight. Funding provided by the Holstein Association USA Research Program and L.E. “Red” Larson Endowment.

Satellite cell (SC) activation is defined as the time frame during which the stem cell becomes poised to reenter G1of the cell cycle. The growth factors and events leading to full mitotic activation in equine SCs remain largely unknown. Insulin-like growth factor I(IGF-I), hepatocyte growth factor(HGF), and fibroblast growth factor 2(FGF2) are sequentially transcribed during the muscle repair and recovery period following strenuous exercise in adult horses. Expression of IGF-Ioccurs within 24 h of the postexercise recovery period suggesting it may affect early SC actions. As a first step, gluteus medius muscle cryosections from adult horses (n= 9) were examined for the presence of central nuclei (CN), a marker of SC addition to the fiber. Results demonstrate few CN fibers prior to exercise with a 3-fold increase (P= 0.05) 24 h postexercise. Cultures of SC (n= 4 isolates) were treated with 100 ng/mL IGF-I for varying times prior to measurement of myogenic events. Results demonstrate that IGF-I does not affect the initial lag period, proliferation, or subsequent differentiation of equine SC in vitro (P> 0.05). However, media containing a combination of IGF-I and 10 ng/mL FGF2 and 25 ng/mL HGF hastens (P< 0.05) the time to S-phase entry in fresh isolates of SCs. Media supplementation with optimal concentrations of FGF2, HGF, or a combination of HGF and FGF2 suppresses (P< 0.05) the percentage of myogenin immunopositive SCs to levels below that found in control- or IGF-I-treated SCs. These results provide new insight into the combinatorial roles growth factors play during equine SC myogenesis.Satellite cells are the resident stem cells found within skeletal muscle. Following strenuous exercise, the cells become mitotically active to supply progenitors for muscle repair. The signals responsible for their exit from the dormant state are largely unknown. Hepatocyte growth factor (HGF), fibroblast growth factor 2 (FGF2), and insulin-like growth factor I (IGF-I) are located within the local environment postexercise suggesting their involvement in mitotic activation. Treatment of satellite cells in vitro with optimal concentrations of HGF, FGF2, or IGF-I did not affect transition into the cell cycle. By contrast, inclusion of all three growth factors in the media caused an increase in the numbers of activated satellite cells. The combination of factors suppressed expression of myogenin, the requisite transcriptional mediator of differentiation. Although IGF-I stimulates myogenin expression in other muscle cell types, a similar response was not observed in equine satellite cells. These results support a role for HGF, FGF2, and IGF-I during the initial postexercise repair period in horses.Combinations of growth factors are required for optimal muscle stem cell activity in vitro.

Circulating memory CD8 T cell trafficking and protective capacity during liver-stage malaria infection remains undefined. We find that effector memory CD8 T cells (Tem) infiltrate the liver within 6 hours after malarial or bacterial infections and mediate pathogen clearance. Tem recruitment coincides with rapid transcriptional upregulation of inflammatory genes in Plasmodium-infected livers. Recruitment requires CD8 T cell-intrinsic LFA-1 expression and the presence of liver phagocytes. Rapid Tem liver infiltration is distinct from recruitment to other non-lymphoid tissues in that it occurs both in the absence of liver tissue resident memory “sensing-and-alarm” function and ∼42 hours earlier than in lung infection by influenza virus. These data demonstrate relevance for Tem in protection against malaria and provide generalizable mechanistic insights germane to control of liver infections.

Detailed single-cell RNA-sequencing analysis of skin and blood from a patient with DRESS, a severe adverse drug reaction, leads to a personalized, hypothesis-driven treatment.

The COVID-19 pandemic forced institutions to move to online learning abruptly during the spring 2020 semester. As a result of this swift change, many microbiology laboratory courses chose to switch all in-class learning activities to simulations.

Postnatal rat retinal ganglion cells (RGCs) were identified with specific fluorescent labels and placed in culture. Under these conditions, the outgrowth of processes by RGCs was found to be promoted to a far greater degree by acidic fibroblast growth factor (aFGF) than by basic fibroblast growth factor (bFGF). The effect of aFGF and bFGF on process extension by solitary RGCs was quantified after 24 hr in culture, a time when neither a FGF nor bFGF enhanced RGC survival. The action of aFGF on process outgrowth was markedly potentiated by the addition of heparin (10 micrograms/ml) to the medium, but heparin alone had no effect. In the presence of heparin, half-maximal process outgrowth occurred at an aFGF concentration of less than 20 pg/ml (1 pM). Since all of the centrally projecting processes have already been formed in the living animal prior to use (at 7-12 days of age), at least a portion of the process outgrowth in culture appears to represent a regenerative phenomenon. Statistical analysis of the increase in process growth revealed that aFGF with heparin contributed to both neurite initiation and elongation. The mean number of glial cells, identified with polyclonal antiserum against glial fibrillary acidic protein, was slightly increased in cultures receiving aFGF plus heparin, but this effect was variable, and these glial cells were not in contact with the solitary RGCs that were scored for regeneration of processes. Thus, glial cells probably did not exert a direct physical influence on the degree of process outgrowth observed in the solitary RGCs, although a humoral effect cannot be totally excluded. These results suggest that aFGF has a potent influence on the outgrowth of processes by a neuron in the mammalian central nervous system. The potentiation of this effect by heparin leads us to speculate that the interaction of aFGF with a heparin-like molecule located in the extracellular matrix (such as heparan sulfate proteoglycan) may produce physiological effects in vivo. Furthermore, the lack of a substantial effect of bFGF in this system under these conditions shows that a specific population of mammalian central neurons may be differentially influenced by these two closely related peptide growth factors.